IRF-1 expression is essential for natural killer cells to suppress metastasis
Menée à l'aide d'un modèle murin de métastases pulmonaires, cette étude met en évidence le rôle joué par l'expression du facteur de transcription IRF-1 dans le contrôle du processus métastatique par les cellules NK
Interferon-γ (IFN-γ) promotes tumoral immune surveillance but its involvement in controlling metastasis is less clear. Using a mouse model of pulmonary metastasis, we show here that local IFN-γ treatment inhibits formation of metastasis through its regulation in tumor cells of IRF-1, an IFN-γ induced transcription factor that is a pivotal regulator of inflammation and infection. IRF-1 blockade abolished the inhibitory effect of IFN-γ on tumor metastasis, whereas ectopic expression of IRF-1 phenocopied the inhibitory effects of IFN-γ. IRF-1 did not affect the survival of tumor cells in the circulation or their infiltration into the lungs, but it was essential to support the pulmonary attraction and activation of natural killer immune cells (NK cells). Depleting NK cells from mice abolished the protective effect of IFN-γ or IRF-1 on metastasis. In addition, cytotoxicity assays revealed that tumor cells expressing IRF-1 were targeted more effectively by NK cells than IRF-1 non-expressing cells. Moreover, NK cells isolated from lungs inoculated with IRF-1 expressing tumor cells exhibited greater cytotoxic activity. Mechanistic investigations revealed that IRF-1-induced NK cell cytotoxicity was independent of perforin and granzyme B but dependent upon the NK cell activating receptor DNAM-1. Taken together, our findings establish IRF-1 as an essential mediator of the crosstalk between tumor cells and NK cells that mediate immune surveillance in the metastatic niche.